Cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from N-allyl enamines

Article abstract of DOI:10.1016/j.tet.2014.08.043

An efficient iodine-mediated cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from easily prepared N-allyl enamines has been developed. The advantages of the reaction include facilitative preparation of substrates 3a-t, good functional group tolerance and transition-metal-free conditions.

Full text of DOI:10.1016/j.tet.2014.08.043

Tetrahedron xxx (2014) 1e8
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Tetrahedron
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Cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives
from N-allyl enamines
,
Sheng-Xian Zhai a, Hong-Ru Dong a, Zi-Bao Chen a, Yi-Ming Hu b, Heng-Shan Dong a
*
a College of Chemistry and Chemical Engineering, State Key Laboratory of Applied Organic Chemistry, Institute of Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, PR China
b The School of Nuclear Science and Technology, Lanzhou University, Lanzhou, Gansu 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient iodine-mediated cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from easily
prepared N-allyl enamines has been developed. The advantages of the reaction include facilitative
preparation of substrates 3aet, good functional group tolerance and transition-metal-free conditions.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 8 March 2014
Received in revised form 14 August 2014
Accepted 18 August 2014
Available online xxx
Keywords:
Iodine-mediated
Cascade reaction
N-Allyl enamines
3-Aza-bicyclo[3.1.0]hex-2-enes
Methodology
1. Introduction
Converting readily available reactants into complex molecular
architectures, through multistep transformations in a one-pot
fashion, namely cascade or domino reaction, are becoming in-
creasingly interests to the construction of natural products and
designed molecules.1 Nitrogen-containing heterocycles (azahe-
terocycle compounds) are such molecules awaiting efficient syn-
thetic methods, more and more chemists have focused on this in
the past decades. For example, the diH-pyrrole scaffolds are very
common in drug molecules, which possess various biological ac-
tivities, such as inhibitors for the microsomal prostaglandin E2,
anti-malarial, anti-depressant, anti-hypertensive, anti-hypoglyce-
mic.2 Particularly, fused-ring and bridge-ring moieties, such as 3-
aza-bicyclo[3.1.0]hexane-2-carboxylic acid derivatives have been
found to serve as an effective plant male gametocide, hepatitis C
protease inhibitors and so on.3 Although, various methods for the
synthesis of azaheterocycle have been reported to date,4 there re-
mains a demand for versatile methodologies to construct azahe-
terocycles. Very recently, Chiba and co-workers have developed an
efficient copper-mediated 3-aza-bicyclo[3.1.0]hex-2-enes core
synthesis from N-allyl enamine carboxylates5 (Scheme 1A), and
Scheme 1. Various methods for 3-aza-bicyclo[3.1.0]hex-2-ene derivatives synthesized.
they have realized the intramolecular oxidative-coupling trans-
formation by using stoichiometric amount of copper salts.
Even though the power of transition-metal catalysis has been
well-demonstrated in synthesis, and that, if a reaction promoted by
transition-metals can be replaced by metal-free conditions with the
same efficiency, the latter will have greater advantage in organic
synthesis. Thereafter, some transition-metal-free reactions were
designed and investigated. It was widely known that iodine
* Corresponding author. Tel.: þ86 (0)931 891 2586; fax: þ86 (0)931 891 2582;
e-mail addresses: donghengshan@lzu.edu.cn, donghengshanlz@163.com (H.-S.
Dong).
http://dx.doi.org/10.1016/j.tet.2014.08.043
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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2
S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
compounds6,7 are inexpensive and less air sensitive, and potentially
promote the transformation to 3-aza-bicyclo[3.1.0]hex-2-enes core
skeleton. Herein, we report a novel and efficient iodine-promoted
3-aza-bicyclo[3.1.0]hex-2-enes skeleton construction in a one-pot
fashion (Scheme 1B).
Table 2
Scope of iodine-mediated 3-aza-bicyclo[3.1.0]hex-2-enes synthesisa
2. Results and discussion
An expeditious synthesis of 3-aza-bicyclo[3.1.0]hex-2-enes core
skeleton achieved by a two-step reaction, involving the coupling of
Entry
1.
Enamines 3aet
Products 4aes/yield
a
-EWG ketones with 3-aminopropene followed by electrophilic
cyclization.7
a-EWG ketones could be synthesized by a method
developed by Balamurugan and Li in 75e90% overall yield.8,9 Var-
ious substituted 3aet are thus prepared to explore the scope and
generality of the methodology, respectively.
To examine the hypothesis, the (Z)-ethyl 3-(allylamino)-3-
phenylacrylate (3a, 0.2 mmol) was employed as a model sub-
strate, which was synthesized by the reaction of allylamine and
ethyl 3-oxo-3-phenylpropanoate. Firstly, elemental iodine was in-
vestigated and delightedly, 4a was isolated in 10% yield when the
reaction was performed under 120 mol % iodine, 120 mol % K2CO3,
at room temperature in DMF (Table 1, entry 2). When the reaction
was carried out at 100 ꢀC, we got 4a in 44% yield and a by-product
(Table 1, entry 3). When the reaction was carried out with 120 mol %
iodine, 120 mol % K2CO3, at 100 ꢀC in DMF under the atmosphere of
Argon, 4a was isolated in 72% yield (Table 1, entry 1). However,
a lower yield of 4a (34%) was achieved when the reaction was
employed at 1 atm O2 (Table 1, entry 4). Other bases, such as
Na2CO3, NaHCO3, and Ag2CO3, DABCO, Et3N were also explored and
affording lower yields of 4a (Table 1, entries 5e9), while, Cs2CO3
gave a comparable yield of 4a (Table 1, entry 10). Product 4a cannot
be observed in the absence of I2 or base (entries 11 and 12).
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
3b (R¼4-MeO; EWG¼eCO2Me)
3c (R¼2-F; EWG¼eCOOEt)
3d (R¼H; EWG¼eCN)
4b 92%
4c 41%
4d 66%
4e 74%
4f 82%
4g 46%
4h 75%
4i 66%
4j 47%
4k 81%
4l 65%
4m 46%
4n 73%
4o 62%
4p 46%
4q 64%
4r 90%
3e (R¼4-Me; EWG¼eCN)
3f (R¼3-Me; EWG¼eCN)
3g (R¼2-Me; EWG¼eCN)
3h (R¼4-MeO; EWG¼eCN)
3i (R¼3-MeO; EWG¼eCN)
3j (R¼2-MeO; EWG¼eCN)
3k (R¼4-Cl; EWG¼eCN)
3l (R¼3-Cl; EWG¼eCN)
3m (R¼2-Cl; EWG¼eCN)
3n (R¼4-Br; EWG¼eCN)
3o (R¼3-Br; EWG¼eCN)
3p (R¼2-Br; EWG¼eCN)
3q (R¼4-I; EWG¼eCN)
3r (R¼3-F; EWG¼eCN)
Table 1
19.
The optimization of the reaction conditionsa
20.
a
Reaction conditions: 3a (0.2 mmol), base (0.24 mmol), I2 (0.24 mmol), DMF
(2 mL), reaction time: 12 h, reaction temperature: 100 ꢀC, under the atmosphere of
Ar. Isolated yield.
Entry
Oxidant
Base (120 mol %)
Temp (ꢀC)
Yieldd (%)
1
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
K2CO3
K2CO3
K2CO3
K2CO3
Ag2CO3
DABCO
Na2CO3
Et3N
100
rt
72
10
44
34
0
24
46
5
2b
3b
4c
5
100
100
100
100
100
100
100
100
100
100
electron-donating or electron-withdrawing groups in their ortho-,
meta- or para-position of the phenyl group, could transform into
the corresponding product with moderate to good yields. This re-
sult showed that phenyl group containing electron-donating
groups exhibited very similar reactivity in comparison to those
bearing electron-withdrawing group. Because of steric hindrance,
both electron-donating and electron-withdrawing groups in the
ortho-position of the phenyl group in compounds (3c, 3g, 3j, 3m,
3p) gave lower yields. When R is furanyl the corresponding product
4r was obtained in good yield (82%). When 3t was explored under
the standard reaction conditions, the corresponding product 4t was
not obtained at all.
6
7
8
9
10
11
12
NaHCO3
Cs2CO3
53
74
0
K2CO3
0
a
Reaction conditions: 3a (0.2 mmol), base (0.24 mmol), I2 (0.24 mmol), DMF
(2 mL), reaction time: 12 h, reaction temperature: 100 ꢀC, under the atmosphere of
Ar.
b
Open to air.
Under 1 atm O2.
Isolated yield.
c
d
In order to demonstrate the practicality of the synthesis strat-
egy, a large scale (ꢁ10) synthesis was also performed. When 3-
(allylamino)-3-(3-methoxyphenyl)acrylonitrile (3i) was carried out
in larger scale under the standard conditions, the cascade reaction
also proceeded smoothly and was able to afford the desired product
4i in 67% yield (Scheme 2).
Under the standard reaction conditions, the scope and limita-
tion of the reaction were explored and the results were shown in
Table 2. The iodine promoted cascade reaction worked smoothly,
and gave the corresponding 3-aza-bicyclo[3.1.0]hex-2-enes in
moderate to good yields. For example, compounds 3, bearing either
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S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
3
chromatography. IR spectra were recorded with an FTIR spec-
trometer as KBr plates or as thin films and peaks are reported in
cmꢂ1 1H NMR and 13C NMR spectra were recorded on a Bruker
.
AVANCE III 400 NMR spectra instrument was recorded on
(400 MHz for 1H and 100 MHz for 13C). Chemical shifts (
d
) were
measured in parts per million (ppm) relative to TMS
d
¼0 ppm for
1H or to chloroform
d
¼77.0 ppm for 13C as internal standard. Data
are reported as follows: chemical shift, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling constants,
J, are reported in hertz (Hz). mass spectrum was recorded on an
Esquire 6000 spectrometer (EI at 70eV), melting points (mp) were
measured on an XT4-100x microscopic melting point apparatus
and are uncorrected, high-resolution mass spectra were measured
with MICRO-TOF QII (ESI).
Scheme 2. Large-scale preparation of 4i.
A mechanism of this iodine promoted cascade reaction is shown
in Scheme 3.7f,g,10,11 Initially, iodocyclization of the allyl group to
form a three-membered-cycle iodonium A, then, an intramolecular
nucleophilic attack of the iodonium A could afford the ammonium
ion B. Under the effort of base, the ammonium ion B can be
transformed into carbon anion D. Then, an intramolecular nucleo-
philic substitution of the intermediate D, would finally lead to the
desired product 4.
4.2. General procedure for the preparation of a-EWG ketones
(2be2s)
A solution of dimethyl carbonate/methyl cyanide (15 mmol) in
toluene (20 mL) was treated with 1-(4-methoxyphenyl)ethanone/
substituted ester (1be1s) (10 mmol), then sodium hydride
(20 mmol, 60%) was added. The reaction mixture was refluxed until
TLC indicated the total consumption of the ester. After cooling, the
mixture was treated with ice-water (100 mL), acidified with 2 M
HCl (to pH 2e3) and extracted with ethyl acetate (100 mLꢁ3). The
combined organic layer was dried over sodium sulfate and the
solvent was removed under reduced pressure. The given residue
was purified by column chromatography using a mixture of pe-
troleum ether and ethyl acetate as eluent to afford 2be2s in
50e90% yield.
4.3. General procedure for the preparation of compounds
3aes
A mixture of ethyl 3-oxo-3-phenylpropanoate (2a) (1.73 mL,
10.00 mmol) and allylamine [(3.75 mL, 50.00 mmol) neutralized
with acetic acid (2.86 mL, 50.00 mmol)] in ethanol (10 mL) was
heated to reflux for 3 h. The resulting mixture was concentrated
and the residue was taken up in CH2Cl2. The organic layer was
washed with 5% HCl and water, dried over MgSO4 and concen-
trated. Purification of the crude product by flash column chroma-
tography (silica gel; petroleum ether/ethyl acetate¼95:5) afforded
3a (2.08 g, 9.00 mmol) in 90% yield as a colourless liquid.
When treated with 2c, it afforded 3c instead of 3-(allylamino)-3-
(2-fluorophenyl) acrylonitrile.
Scheme 3. Mechanism for the iodine promoted cascade reaction.
3. Conclusions
In summary, an efficient, iodine-mediated domino reaction has
been employed in the synthesis of 3-aza-bicyclo[3.1.0]hex-2-enes
derivatives from easily prepared N-allyl enamines. In this meth-
odology, pre-functionalization of the reaction centre is not re-
quired, which makes the preparation of substrates from available
starting materials more facilitative. Furthermore, good functional
group tolerance allows the formation of various substituted 3-aza-
bicyclo[3.1.0]hex-2-enes to form from corresponding substrates.
The application of iodine promoted cascade reaction in the syn-
thesis of heterocycle compounds is currently undergoing in our
laboratory.
4.3.1. (Z)-Ethyl 3-(allylamino)-3-phenylacrylate (3a). Colourless oil,
yield: 90%, 1H NMR (400 MHz, CDCl3):
3.653e3.690 (2H, m), 4.634 (2H, q, J¼7.2 Hz), 4.636 (1H, s), 5.105
(1H, dd, J¼1.2, 10.4 Hz), 5.209 (1H, dd, J¼1.2, 17.2 Hz), 5.733e5.827
(1H, m), 7.331e7.407 (5.09H, m), 8.622 (0.89H, br) ppm. 13C NMR
d
1.280 (3H, t, J¼7.2 Hz),
(100 MHz, CDCl3):
d 14.55, 46.75, 58.68, 85.89, 115.74, 127.74,
128.26, 129.20, 135.34, 135.93, 164.77, 170.34 ppm.
4.3.2. (Z)-Methyl
(3b). Lustrous white solid, yield: 78%, mp 50e51 ꢀC, 1H NMR
(400 MHz, CDCl3): 3.682e3.722 (5H, m), 3.825 (3H, s), 4.634 (1H,
3-(allylamino)-3-(4-methoxyphenyl)
acrylate
4. Experimental section
4.1. General information
d
s), 5.115 (1H, dd, J¼0.8, 10.4 Hz), 5.225 (1H, dd, J¼1.2, 16.8 Hz),
5.747e5.840 (1H, m), 6.897 (2H, d, J¼8.8 Hz), 7.295 (2H, d,
J¼8.8 Hz), 8.597 (0.96H, br) ppm. 13C NMR (100 MHz, CDCl3):
All reactions involving air- and moisture-sensitive reagent were
carried out under an argon atmosphere. All chemicals were pur-
chased from Aldrich and used without further purification. Thin-
layer chromatography (TLC) was performed using 60 mesh
silica gel plates visualized with short-wavelength UV light
(254 nm). Silica gel 60 (230e400 mesh) was used for column
d
46.81, 50.20, 55.20, 85.12, 113.66, 115.68, 128.08, 129.15, 135.39,
160.41, 164.83, 170.67 ppm; IR (neat, cmꢂ1) 3288, 2927, 2847, 1655,
1610, 1486, 1463, 1291, 1251, 1168, 1029, 839, 791. MS (m/z) [Mþ
,
ꢃ
247] (Mþ, 55%), 246 (20%), 232 (12%), 216 (12%), 189 (13%), 188
(100%),186 (13%),174 (35%),134 (24%),133 (34%),133 (34%), 89 (7%),
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4
S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
77 (9%), 41 (12%). HRMS (ESI) calcd for C14H18NO3 [MþH]þ
129.61, 130.31, 130.54, 132.12, 134.16, 135.42, 135.46, 135.55,
162.09 ppm; IR (neat, cmꢂ1) 3404, 3306, 3066, 2925, 2191,þ1589,
1536, 1489, 1304, 1248, 992, 770, 733. MS (m/z) [Mþꢃ, 198] (M , 7%),
177 (9%), 183 (11%), 159 (12%), 158 (100%), 157 (12%), 143 (18%), 118
(8%), 115 (12%), 91 (7%), 77 (4%), 41 (13%). HRMS (ESI) calcd for
248.1287, found 248.1278.
4.3.3. Ethyl 3-(allylamino)-3-(2-fluorophenyl)acrylate (3c). Light
yellow solid, yield: 89%, mp 59e60 ꢀC (major/minor¼9:1), 1H NMR
(400 MHz, CDCl3):
d
1.402 (3.09H, t, J¼7.2 Hz), 3.737 (1.77H, t,
C
13H15N2 [MþH]þ 199.1235, found 199.1242.
J¼5.6 Hz), 3.807e3.830 (0.47H, m), 4.033e4.099 (2.93H, m), 4.685
(0.83H, br), 5.129e5.380 (2.25H, m), 5.776e5.904 (1.0H, m),
6.884e7.002 (2.05H, m), 7.216 (0.19H, dd, J¼1.6, 7.6 Hz),
4.3.8. 3-(Allylamino)-3-(4-methoxyphenyl)acrylonitrile (3h). Yellow
oil, yield: 85% (major/minor¼3:1), 1H NMR (400 MHz, CDCl3):
7.332e7.410 (1.88H, m) ppm. 13C NMR (100 MHz, CDCl3):
d
14.70,
d 3.710 (1.46H, s), 3.801 (3H, s), 3.942e4.007 (1.60H, m), 4.742
46.18, 46.99, 62.40, 63.26, 64.16, 111.99, 112.59, 116.76, 117.48,
120.42, 120.57, 120.64, 121.34, 124.51, 129.98, 130.40, 131.12, 131.22,
(0.76H, br), 4.937 (0.25H, br), 5.181e5.291 (2H, m), 5.800e5.923
(1H, m), 6.884 (1H, d, J¼8.0 Hz), 6.905 (1H, d, J¼8.8 Hz), 7.327
(0.54H, d, J¼8.8 Hz), 7.488 (1.51H, d, J¼8.0 Hz) ppm. 13C NMR
132.17, 134.31, 155.50, 155.69, 160.11, 161.33 ppm; IR (neat, cmꢂ1
)
,
3311, 2922, 2192, 1591, 1526, 1491, 1246, 922, 754. MS (m/z) [Mþ
(100 MHz, CDCl3): d 46.07, 47.03, 55.16, 60.74, 61.75, 113.84, 113.88,
ꢃ
249] (Mþ, 0.3%), 228 (4%), 199 (5%), 189 (13%), 188 (100%), 187 (10%),
162 (20%), 160 (34%), 159 (25%), 158 (10%), 120 (9%), 95 (9%), 57
(12%), 41 (30%). HRMS (ESI) calcd for C14H17FNO2 [MþH]þ 250.1243,
found 250.1249.
116.68, 117.51, 120.42, 121.91, 127.74, 128.41, 129.10, 132.20, 134.09,
160.95, 161.10, 161.77 ppm; IR (neat, cmꢂ1) 3327, 2839, 2190, 1610,
1593, 1528, 1506, 1253, 1180, 1031, 838, 746. MS (m/z) [Mþꢃ, 214]
(Mþ, 4%), 213 (7%), 199 (5%), 175 (9%), 174 (100%), 159 (13%), 158
(8%), 134 (16%), 115 (4%), 77 (4%), 41 (5%). HRMS (ESI) calcd for
4.3.4. 3-(Allylamino)-3-phenylacrylonitrile (3d). Red oil, yield:
C
13H15N2O [MþH]þ 215.1184, found 215.1180.
66% (major/minor¼4:1), 1H NMR (400 MHz, CDCl3):
d 3.753 (1.66H,
t, J¼5.6 Hz), 3.999 (0.7H, t, J¼5.6 Hz), 4.069 (0.8H, s), 4.531 (0.76H,
br), 4.889 (0.2H, br), 5.201e5.338 (2H, m), 5.833e5.930 (1H, m),
7.388e7.463 (3.58H, m), 7.546e7.570 (1.58H, m) ppm. 13C NMR
4.3.9. 3-(Allylamino)-3-(3-methoxyphenyl)acrylonitrile (3i). Light
yellow oil, yield: 88% (major/minor¼4:1), 1H NMR (400 MHz,
CDCl3):
d
3.730 (1.63H, t, J¼5.2 Hz), 3.809e3.818 (3.03H, m),
(100 MHz, CDCl3):
d
46.29, 47.21, 62.19, 63.23, 117.03, 118.03, 120.05,
4.012e4.032 (1.41H, m), 4.645 (0.81H, br), 4.921 (0.16H, br),
5.200e5.317 (2.07H, m), 5.814e5.931 (1.00H, m), 6.907e6.986
(1.40H, m), 7.076e7.125 (1.66H, m), 7.267e7.346 (1.09H, m) ppm.
121.30, 127.16, 127.74, 128.74, 128.79, 130.31, 130.41, 132.09, 134.11,
135.72, 136.28, 162.01 ppm; IR (neat, cmꢂ1) 3321, 2921, 2191, 1592,
1567, 1525, 1492, 1304, 923, 700. MS (m/z) [Mþꢃ, 184] (Mþ, 7%), 183
(11%), 169 (8%), 156 (7%), 145 (9%), 144 (100%), 143 (12%), 128 (7%),
104 (14%), 77 (14%), 41 (10%). HRMS (ESI) calcd for C12H13N2
[MþH]þ 185.1079, found 185.1072.
13C NMR (100 MHz, CDCl3):
d 46.19, 47.09, 55.32, 61.79, 62.78,
112.71, 113.14, 115.69, 116.18, 116.91, 117.88, 119.30, 119.88, 120.08,
121.31, 129.82, 132.04, 134.06, 136.85, 137.61, 159.53, 159.58,
161.78 ppm; IR (neat, cmꢂ1) 3327, 2931, 2838, 2191, 1þ595, 1573,
1526, 1289, 1239, 1047, 791, 742. MS (m/z) [Mþꢃ, 214] (M , 6%), 213
(7%), 199 (5%), 174 (14%), 174 (100%), 159 (14%), 143 (8%), 134 (13%),
115 (5%), 77 (6%), 41 (7%). HRMS (ESI) calcd for C13H15N2O [MþH]þ
215.1184, found 215.1183.
4.3.5. 3-(Allylamino)-3-p-tolylacrylonitrile (3e). Light yellow solid,
yield: 70%, mp 83e84 ꢀC (major/minor¼4:1), 1H NMR (400 MHz,
CDCl3):
d 2.372 (3H, s), 3.724 (1.74H, s), 3.976e4.009 (1.38H, m),
4.589 (0.82H, br), 4.887 (0.17H, br), 5.187e5.308 (2H, m),
5.811e5.908 (1H, m), 7.178e7.288 (2.53H, m), 7.440 (1.70H, d,
4.3.10. 3-(Allylamino)-3-(2-methoxyphenyl)acrylonitrile (3j). Light
yellow solid, yield: 67%, mp 73e74 ꢀC (major/minor¼3:1), 1H NMR
J¼7.6 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 21.27, 46.20, 47.14,
61.53, 62.52, 116.86, 117.76, 120.25, 121.60, 126.99, 127.58, 129.35,
(400 MHz, CDCl3): d 3.718e3.784 (2.07H, m), 3.819e3.84 (3.30H,
132.20, 132.80, 134.15, 140.54, 162.10 ppm; IR (neat, cmꢂ1) 3325,
m), 4.089 (0.74H, s), 4.667 (0.74H, br), 5.119e5.353 (2.36H, m),
5.753e5.898 (1.00H, m), 6.907e7.011 (2.09H, m), 7.197 (0.28H, dd,
J¼1.6, 7.6 Hz), 7.361e7.401 (1.76H, m) ppm. 13C NMR (100 MHz,
2923, 2191, 1593, 1562, 1527, 1505, 1304, 923, 825. MS (m/z) [Mþ
,
ꢃ
198] (Mþ, 7%),197 (5%),183 (7%),159 (10%),158 (100%),157 (9%),143
(15%), 115 (8%), 118 (13%), 91 (2%), 77 (4%), 41 (10%). HRMS (ESI)
calcd for C13H15N2 [MþH]þ 199.1235, found 199.1238.
CDCl3):
d 46.07, 46.84, 55.47, 55.62, 62.49, 63.18, 110.91, 111.49,
116.59, 117.40, 120.11, 120.65, 121.19, 124.10, 124.31, 129.88, 130.25,
131.15, 131.22, 132.18, 134.30, 156.01, 156.20, 159.82, 161.18 ppm; IR
(neat, cmꢂ1) 3326, 2933, 2839, 2193, 1592, 1522, 1463, 1280, 1250,
1024, 756. MS (m/z) [Mþꢃ, 214] (Mþ, 6%), 199 (4%), 175 (10%), 174
(100%), 159 (15%), 143 (6%), 115 (4%), 77 (6%), 41 (8%). HRMS (ESI)
calcd for C13H15N2O [MþH]þ 215.1184, found 215.1188.
4.3.6. 3-(Allylamino)-3-m-tolylacrylonitrile (3f). Light yellow solid,
yield: 87%, mp 50e51 ꢀC (major/minor¼4:1), 1H NMR (400 MHz,
CDCl3):
d
2.379 (3.09H, d, J¼1.6 Hz), 3.727 (1.73H, d, J¼4.0 Hz),
3.991e4.030 (1.39H, m), 4.613 (0.82H, br), 4.897 (0.17H, br),
5.196e5.321 (2.08H, m), 5.808e5.928 (1.0H, m), 7.182 (0.41H, d,
J¼8.8 Hz), 7.244e7.341 (3.75H, m) ppm. 13C NMR (100 MHz, CDCl3):
4.3.11. 3-(Allylamino)-3-(4-chlorophenyl)acrylonitrile (3k). Yellow
solid, yield: 77%, mp 102e103 ꢀC (major/minor¼9:1), 1H NMR
d
21.29, 46.21, 47.14, 61.62, 116.93, 117.86, 121.52, 124.15, 124.84,
127.68, 128.22, 128.58, 128.60, 131.02, 131.08, 132.11, 134.09, 135.63,
138.48, 138.55, 162.23 ppm; IR (neat, cmꢂ1) 3411, 3325, 2923, 2192,
2595, 1574, 1524, 1304, 921, 794, 738. MS (m/z) [Mþꢃ, 198] (Mþ, 6%),
197 (8%), 183 (7%), 159 (10%), 158 (100%), 157 (10%), 156 (8%), 143
(16%), 118 (11%), 115 (7%), 91 (9%), 77 (3%), 41 (9%). HRMS (ESI) calcd
for C13H15N2 [MþH]þ 199.1235, found 199.1230.
(400 MHz, CDCl3):
d
3.729 (1.78H, t, J¼5.2 Hz), 3.961 (0.50H, t,
J¼6.0 Hz), 4.046 (0.87H, s), 4.650 (0.85H, br), 4.916 (0.14H, br),
5.200e5.313 (2H, m), 5.807e5.903 (1H, m), 7.321e7.404 (2.36H,
m), 7.484 (1.73H, d, J¼8.0 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d
46.28, 47.14, 62.42, 63.63, 117.11, 118.07, 119.67, 121.10, 128.51,
128.99, 129.19, 131.91, 133.91, 133.98, 134.56, 136.38, 160.86 ppm;
IR (neat, cmꢂ1) 3426, 3311, 3062, 2193, 1591,1528,1489,1267, 1092,
835, 738. MS (m/z) [Mþꢃ, 218] (Mþ, 8%), (Mþ2, 3%), 217 (10%), 203
(7%), 180 (30%), 178 (100%), 143 (41%), 138 (15%), 75 (8%), 43 (19%).
4.3.7. 3-(Allylamino)-3-o-tolylacrylonitrile (3g). Light yellow solid,
yield: 65%, mp 65e66 ꢀC (major/minor¼4:1), 1H NMR (400 MHz,
CDCl3):
d
2.306 (0.47H, s), 2.364 (2.53H, s), 3.648e3.775 (2.18H, m),
HRMS (ESI) calcd for
219.0679.
C
12H12ClN2 [MþH]þ 219.0689, found
4.124 (0.83H, s), 4.469 (0.81H, br), 5.062 (0.14H, br), 5.127e5.320
(2.07H, m), 5.712e5.897 (1.0H, m), 7.126e7.326 (4.19H, m) ppm. 13
NMR (100 MHz, CDCl3): 18.83, 18.84, 46.12, 46.57, 62.87, 63.51,
116.86, 117.86, 119.68, 120.73, 125.82, 125.95, 128.18, 128.32, 129.43,
C
d
4.3.12. 3-(Allylamino)-3-(3-chlorophenyl)acrylonitrile
(3l). Light
yellow oil, yield: 82% (major/minor¼6:1), 1H NMR (400 MHz,
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S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
5
CDCl3):
d
3.726 (1.71H, t, J¼5.2 Hz), 3.967e3.992 (0.52H, m), 4.058
(100%), 144 (20%), 143 (54%), 77 (13%), 41 (13%). HRMS (ESI) calcd
(0.85H, s), 4.689 (0.84H, br), 4.932 (0.16H, br), 5.210e5.314 (2.04H,
for C12H12BrN2 [MþH]þ 263.0184, found 263.0188.
m), 5.802e5.919 (1.0H, m), 7.268e7.497 (4.12H, m) ppm. 13C NMR
(100 MHz, CDCl3):
d
46.25, 47.10, 62.51, 62.64, 117.18, 118.04,
4.3.17. 3-(Allylamino)-3-(4-iodophenyl)acrylonitrile (3q). Light yel-
low solid, yield: 82%, mp 102e103 ꢀC (major/minor¼4:1), 1H NMR
118.08, 119.58, 120.86, 125.32, 126.25, 127.25, 127.75, 130.04,
130.39, 131.83, 133.80, 134.57, 134.64, 137.24, 137.98, 160.51,
160.90 ppm; IR (neat, cmꢂ1) 3317, 3068, 2924, 2194, 1589þ, 1562,
1528, 1474, 1304, 1248, 793, 702. MS (m/z) [Mþꢃ, 218] (M , 6%),
(Mþ2, 2%), 180 (28%), 178 (100%), 143 (30%), 138 (13%), 127 (7%), 77
(4%), 41 (28%). HRMS (ESI) calcd for C12H12ClN2 [MþH]þ 219.0689,
found 219.0686.
(400 MHz, CDCl3):
d 3.724e3.736 (1.74H, m), 3.942e3.978 (0.54H,
m), 4.043 (0.84H, d, J¼3.6 Hz), 4.622 (0.84H, br), 4.899 (0.17H, br),
5.200e5.311 (2H, m), 5.803e5.904 (1H, m), 7.129 (0.34H, d,
J¼8.0 Hz), 7.287 (1.68H, t, J¼6.4 Hz), 7.724e7.778 (1.98H, m) ppm.
13C NMR (100 MHz, CDCl3):
d 46.29, 47.15, 62.41, 63.64, 96.71, 117.14,
118.10, 118.13, 121.02, 121.06, 127.70, 128.74, 128.81, 129.44, 131.89,
133.91, 135.03, 137.92, 160.97 ppm; IR (neat, cmꢂ1) 3318, 3066,
2923, 2193, 1587, 1527, 1483, 1303, 1006, 829, 738. MS (m/z) [Mþ
,
ꢃ
4.3.13. 3-(Allylamino)-3-(2-chlorophenyl)acrylonitrile (3m). Light
yellow solid, yield: 69%, mp 74e75 ꢀC (major/minor¼6:1), 1H NMR
310] (Mþ, 9%), 309 (6%), 271 (13%), 270 (100%), 230 (10%), 168 (5%),
144 (20%), 143 (35%), 127 (6%), 76 (9%), 41 (13%). HRMS (ESI) calcd
for C12H12IN2 [MþH]þ 311.0045, found 311.0034.
(400 MHz, CDCl3):
d
3.750 (2.03H, t, J¼5.6 Hz), 3.818 (0.16H, s),
4.165 (0.86H, s), 4.579 (0.84H, br), 5.071 (0.13H, br), 5.137e5.364
(2.17H, m), 5.762e5.905 (1.0H, m), 7.254e7.454 (4.20H, m) ppm.
13C NMR (100 MHz, CDCl3):
d
46.27, 46.81, 63.78, 64.54, 117.17,
4.3.18. 3-(Allylamino)-3-(furan-2-yl)acrylonitrile (3r). Yellow oil,
117.93, 120.21, 126.92, 127.06, 129.86, 130.09, 130.12, 130.48,
130.85, 131.02, 131.88, 132.11, 133.92, 134.52, 159.57, 160.59 ppm;
IR (neat, cmꢂ1) 3418, 3325, 3071, 219þ5, 1604, 1585, 1523, 1306,
1034, 924, 759. MS (m/z) [Mþꢃ, 218] (M , 6%), (Mþ2, 2%), 217 (9%),
180 (26%), 178 (100%), 143 (36%), 138 (17%), 102 (7%), 77 (4%), 41
(15%). HRMS (ESI) calcd for C12H12ClN2 [MþH]þ 219.0689, found
219.0696.
yield: 65% (major/minor¼9:1), 1H NMR (400 MHz, CDCl3):
d3.755
(1.91H, t, J¼5.2 Hz), 3.975e3.982 (0.9H, m), 4.256 (0.24H, t,
J¼5.2 Hz), 4.358 (0.12H, s), 5.183 (0.10H, br), 5.250e5.365 (2.91H,
m), 5.822e6.001 (1H, m), 6.457e6.470 (0.12H, m), 6.528 (0.88H, dd,
J¼1.2, 3.2 Hz), 6.690 (0.12H, d, J¼3.2 Hz), 7.398 (0.850H, d, J¼3.6 Hz),
7.469 (0.98H, s) ppm. 13C NMR (100 MHz, CDCl3):
d 45.52, 46.48,
58.20, 58.59, 109.68, 111.94, 112.17, 113.16, 117.18, 117.78, 120.48,
121.46, 132.01, 133.47, 142.74, 143.28, 146.31, 148.54, 148.62,
149.24 ppm; IR (neat, cmꢂ1) 3347, 2924, 2190, 1615, 1587, 1556,
1479, 1303, 1024, 749, 593. MS (m/z) [Mþꢃ, 174] (Mþ, 10%), 159 (6%),
145 (6%), 135 (8%), 134 (100%), 118 (13%), 106 (27%), 94 (20%), 79
(12%), 41 (23%). HRMS (ESI) calcd for C10H11N2O [MþH]þ 175.0871,
found 175.0877.
4.3.14. 3-(Allylamino)-3-(4-bromophenyl)acrylonitrile
(3n). Light
yellow solid, yield: 76%, mp 102e103 ꢀC (major/minor¼6:1), 1H
NMR (400 MHz, CDCl3): d 3.731 (1.73H, s), 3.958e3.980 (0.54H, m),
4.052 (0.84H, s), 4.626 (0.81H, br), 4.907 (0.15H, br), 5.160e5.315
(2H, m), 5.810e5.905 (1H, m), 7.270 (0.42H, d, J¼7.6 Hz), 7.420
(1.70H, d, J¼8.4 Hz), 7.520e7.602 (2.0H, m) ppm. 13C NMR
(100 MHz, CDCl3):
d
46.29, 47.15, 62.45, 117.14, 118.12, 119.65, 121.07,
4.3.19. 3-(Allylamino)-3-(3-fluorophenyl)acrylonitrile (3s). Yellow
oil, yield: 78% (major/minor¼6:1), 1H NMR (400 MHz, CDCl3):
124.63, 124.70, 128.51, 128.75, 129.41, 131.67, 131.88, 131.98, 133.90,
134.44, 160.87 ppm; IR (neat, cmꢂ1) 3316, 2192, 1588, 1528, 1486,
1393,1011, 833. MS (m/z) [Mþꢃ, 262] (Mþ, 7%), (Mþ2, 7%), 224 (94%),
222 (100%), 182 (24%), 143 (75%), 127 (13%), 77 (5%), 75 (8%), 41
(22%). HRMS (ESI) calcd for C12H12BrN2 [MþH]þ 263.0184, found
263.0178.
d
3.687 (1.76H, t, J¼5.2 Hz), 3.957e3.991 (1.33H, m), 4.006e5.083
(1H, br), 5.183e5.274 (2H, m), 5.760e5.875 (1H, m), 7.096e7.213
(2.13H, m), 7.285e7.387 (1.95H, m) ppm. 13C NMR (100 MHz,
CDCl3):
d 45.99, 46.76, 61.59, 62.62, 113.58, 113.97, 114.20, 114.75,
114.97, 116.51, 116.82, 116.92, 117.13, 117.55, 119.59, 119.73, 121.11,
122.66, 122.69, 123.53, 123.56, 129.57, 130.17, 130.26, 130.35, 131.82,
133.67, 137.31, 137.39, 138.36, 160.68, 160.96, 163.42, 163.51 ppm; IR
(neat, cmꢂ1) 3425, 3322, 2194, 1598, 1576, 1524, 1268, 1221, 906,
738. MS (m/z) [Mþꢃ, 202] (Mþ, 7%), 187 (6%), 174 (6%), 163 (10%), 162
(100%), 161 (9%), 122 (11%), 95 (8%), 75 (6%), 41 (21%). HRMS (ESI)
calcd for C14H17FNO2 [MþH]þ 250.1243, found 250.1238.
4.3.15. 3-(Allylamino)-3-(3-bromophenyl)acrylonitrile
(3o). Light
yellow solid, yield: 88%, mp 58e59 ꢀC (major/minor¼6:1), 1H NMR
(400 MHz, CDCl3):
d
3.732 (1.71H, t, J¼5.6 Hz), 3.981 (0.56H, t,
J¼5.6 Hz), 4.070 (0.84H, s), 4.631 (0.84H, br), 4.913 (0.16H, br),
5.212e5.319 (2.06H, m), 5.810e5.921 (1.0H, m), 7.250e7.339
(1.30H, m), 7.507 (0.84H, dd, J¼1.2, 8.0 Hz), 7.544e7.589 (1.18H, m),
7.650 (0.81H, s) ppm. 13C NMR (100 MHz, CDCl3):
d
46.29, 47.14,
4.3.20. 3-(Allylamino)-3-(naphthalen-1-yl)acrylonitrile (3t). Yellow
solid, yield: 90% (major/minor¼10:7), 1H NMR (400 MHz, CDCl3):
62.73, 63.85, 117.21, 118.13, 119.52, 120.79, 122.62, 122.68, 125.81,
126.77, 130.14, 130.29, 130.56, 131.83, 133.28, 133.34, 133.81, 137.51,
138.22, 160.39, 160.79 ppm; IR (neat, cmꢂ1) 3315,þ2193, 1587, 1556,
1529,1472,1248, 790, 700. MS (m/z) [Mþꢃ, 262] (M , 8%), (Mþ2, 8%),
225 (11%), 224 (100%), 223 (11%), 222 (100%), 182 (18%), 143 (70%),
77 (5%), 41 (25%). HRMS (ESI) calcd for C12H12BrN2 [MþH]þ
263.0184, found 263.0177.
d
3.601 (1.48H, br), 3.804 (2.02H, m), 3.981 (0.74H, s), 4.320 (1.02H,
s), 4.611 (0.99H, br), 5.088e5.106 (1.56H, m), 5.253e5.345 (2.79H,
m), 5.671e5.766 (0.74H, m), 5.833e5.929 (1H, m), 7.381e7.563
(7.32H, m), 7.853e8.014 (5.44H, m) ppm. 13C NMR (100 MHz,
CDCl3):
d 46.36, 46.97, 64.38, 64.80, 116.93, 118.09, 119.61, 120.54,
124.45, 124.59, 124.97,125.12,126.28,126.35,126.45,126.78,126.99,
127.31, 128.37, 128.45, 129.97, 130.14, 130.29, 130.35, 132.08, 133.16,
133.22, 133.59, 134.23, 161.02 ppm; HRMS (ESI) calcd for C16H15N2
[MþH]þ 235.1235, found 235.1238.
4.3.16. 3-(Allylamino)-3-(2-bromophenyl)acrylonitrile (3p). Yellow
solid, yield: 69%, mp 77e78 ꢀC (major/minor¼6:1), 1H NMR
(400 MHz, CDCl3):
d
3.745 (2.06H, t, J¼5.6 Hz), 3.803 (0.16H, s),
4.154 (0.84H, s), 4.559 (0.84H, br), 5.043 (0.13H, br), 5.141e5.374
(2.07H, m), 5.758e5.918 (1.0H, m), 7.242e7.380 (3.15H, m), 7.609
4.4. General procedures for 3-aza-bicyclo[3.1.0]hex-2-enes
4aes
(0.96H, t, J¼8.0 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 46.30, 46.83,
63.63, 64.42, 117.22, 117.98, 119.24, 120.16, 121.42, 121.63, 127.45,
127.62, 128.68, 130.09, 130.45, 130.93, 131.13, 131.91, 133.04, 133.24,
133.88, 136.14, 136.54, 160.88 ppm; IR (neat, cmꢂ1) 3301, 3070,
2194, 1602, 1584, 1548, 1442, 1257, 1025, 923, 759, 635. MS (m/z)
[Mþꢃ, 262] (Mþ, 8%), (Mþ2, 8%), 225 (9%), 224 (94%), 223 (11%), 222
To a mixture of (Z)-ethyl 3-(allylamino)-3-phenylacrylate 3a
(0.2 mmol), iodine (0.24 mmo), and K2CO3 (0.24 mmol) was added
2.0 mL N,N-dimethylformamide (DMF) under Ar at room temper-
ature. The reaction temperature was raised to 100 ꢀC for 12 h. Then,
the temperature of the reaction was reduced to room temperature.
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6
S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
The resulting reaction solution was quenched with 20 mL aqueous
ammonia (5%) and extracted with ethyl acetate (3ꢁ20 mL). The
extract was washed with brine (2ꢁ20 mL) and dried over Na2SO4.
The solvent was evaporated in vacuo and the residue was purified
by flash column chromatography on silica gel with ethyl acetate/
petroleum ether as an eluent to give the desired product 4a.
NMR (100 MHz, CDCl3): d 21.30, 22.95, 24.77, 29.76, 62.00, 118.73,
125.51, 128.64, 128.71, 131.30, 132.34, 138.56, 168.72 ppm; IR
(neat, cmꢂ1) 2924, 2855, 2235, 1602, 1581, 1329, 1042, 912, 733,
703. HRMS (ESI) calcd for C13H12N2 [MþH]þ197.1079, found
197.1068.
4.4.7. (1S
carbonitrile (4g). Yield: 46%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
*
,5S
*
)-2-o-Tolyl-3-aza-bicyclo[3.1.0]hex-2-ene-1-
4.4.1. (1S
carboxylate (4a).4 Yield: 72%, light yellow solid, mp 51e52 ꢀC (lit.
55e57 ꢀC), 1H NMR (400 MHz, CDCl3):
*
,5S )-Ethyl 2-phenyl-3-aza-bicyclo[3.1.0]hex-2-ene-1-
*
d
1.072 (1H, t, J¼5.2 Hz), 1.916 (1H, dd, J¼4.4, 8.8 Hz), 2.548
d
0.875 (1H, dd, J¼4.4,
(3H, s), 2.822e2.873 (1H, m), 4.009 (1H, d, J¼18 Hz), 4.296 (1H, dd,
5.6 Hz), 1.035 (3H, t, J¼7.2 Hz), 2.117 (1H, dd, J¼4.4, 8.8 Hz),
2.514e2.567 (1H, m), 3.957e4.061 (2H, m), 4.106e4.191 (2H, m),
7.367e7.446 (3H, m), 7.728e7.752 (2H, m) ppm. 13C NMR (100 MHz,
J¼6, 18 Hz), 7.277e7.383 (3H, m), 7.644 (1H, dd, J¼1.6, 7.2 Hz) ppm.
13C NMR (100 MHz, CDCl3):
d 21.02, 23.50, 27.64, 30.09, 62.72,
118.37, 125.92, 129.89, 130.53, 131.22, 131.51, 137.73, 169.95 ppm; IR
(neat, cmꢂ1) 3064, 2956, 2925, 2852, 2234, 1609, 1457, 1322, 1041,
997, 769, 733. HRMS (ESI) calcd for C13H12N2 [MþH]þ197.1079,
found 197.1072.
CDCl3):
d 13.83, 21.42, 31.80, 40.94, 60.90, 61.87, 128.05, 128.07,
130.21, 133.91, 169.85, 172.69, IR (neat, cmꢂ1) 2981, 2923, 1724,
1600, 1574, 1448, 1375, 1345, 1270, 1178, 1156, 1002, 697.
4.4.2. (1S
hex-2-ene-1-carboxylate (4b). Yield: 92%, white solid, mp
66e67 ꢀC, 1H NMR (400 MHz, CDCl3):
*
,5S
*
)-Methyl
2-(4-methoxyphenyl)-3-aza-bicyclo[3.1.0]
4.4.8. (1S
ene-1-carbonitrile (4h). Yield: 75%, colourless oil, 1H NMR
(400 MHz, CDCl3):
*
,5S )-2-(4-Methoxyphenyl)-3-aza-bicyclo [3.1.0]hex-2-
*
d
0.853 (1H, dd, J¼4.4, 5.6 Hz),
d
0.981 (1H, t, J¼5.2 Hz), 1.867 (1H, dd, J¼4.4,
2.105 (1H, dd, J¼4.4, 8.8 Hz), 2.502e2.555 (1H, m), 3.622 (3H, s),
3.842 (3H, s), 4.003 (1H, d, J¼17.6 Hz), 4.126 (1H, dd, J¼6, 17.6 Hz),
6.913 (2H, d, J¼8.8 Hz), 7.698 (2H, d, J¼8.8 Hz) ppm. 13C NMR
8.8 Hz), 2.800 (1H, dd, J¼6, 14 Hz), 3.866 (3H, s), 4.049 (1H, d,
J¼18 Hz), 4.199 (1H, dd, J¼6, 18 Hz), 6.978 (2H, d, J¼8.4 Hz), 7.940
(2H, d, J¼8.4 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 22.94, 24.59,
(100 MHz, CDCl3):
d
21.44, 31.99, 40.54, 52.03, 55.26, 61.46, 113.54,
29.88, 55.39, 61.77, 114.13, 118.94, 124.22, 130.02, 162.23,
167.75 ppm; IR (neat, cmꢂ1) 2925, 2849, 2233, 1605, 1570, 1514,
1333, 1256, 1174, 1030, 1001, 842, 733. HRMS (ESI) calcd for
126.38, 129.71, 161.32, 170.48, 171.64 ppm; IR (neat, cmꢂ1) 3001,
2953, 2922, 2847, 1727, 1606, 1514, 1345, 1272, 1253, 1175, 1155,
1034, 1004, 840, 734. HRMS (ESI) calcd for C14H15NO3 [MþH]þ
246.1130, found 246.1122.
C
13H12N2O [MþH]þ 213.1028, found 213.1020.
4.4.9. (1S
1-carbonitrile (4i). Yield: 66%, colourless solid, mp 65e66 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-2-(3-Methoxyphenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
4.4.3. (1S
ene-1-carboxylate (4c). Yield: 41%, white solid, mp 41e42 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-Ethyl 2-(2-fluorophenyl)-3-aza-bicyclo[3.1.0]hex-2-
d
1.002 (1H, t, J¼5.2 Hz), 1.890 (1H, dd,
d
1.044 (1H, t, J¼5.2 Hz), 1.536 (3H, t,
J¼4.4, 8.8 Hz), 2.796e2.851 (1H, m), 3.866 (3H, s), 4.091 (1H, d,
J¼18 Hz), 4.242 (1H, dd, J¼6, 18 Hz), 7.070 (1H, dd, J¼2.0, 8.0 Hz),
7.393 (1H, t, J¼8.0 Hz), 7.491 (1H, t, J¼2.0 Hz), 7.581 (1H, d,
J¼7.2 Hz), 1.777 (1H, dd, J¼4.4, 8.8 Hz), 2.771e2.826 (1H, m), 4.017
(1H, dd, J¼0.8,17.6 Hz), 4.091e4.244 (3H, m), 6.984 (2H, t, J¼8.8 Hz),
7.435 (1H, dt, J¼1.6, 8.0 Hz), 7.615 (1H, dd, J¼1.6, 7.6 Hz) ppm. 13
C
J¼7.6 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 23.00, 24.84, 29.87,
NMR (100 MHz, CDCl3):
d
14.61, 22.82, 28.79, 30.43, 61.46, 63.81,
55.40, 62.05, 112.42, 118.29, 118.68, 121.00, 129.80, 132.65, 159.83,
168.50 ppm; IR (neat, cmꢂ1) 2926, 2848, 2234, 1602, 1579, 1489,
1461, 1329, 1289, 1246, 1045, 1023, 1000, 789, 733, 702. HRMS (ESI)
calcd for C13H12N2O [MþH]þ213.1028, found 213.1018.
111.72, 119.01, 120.67, 121.38, 130.68, 132.68, 157.72, 168.81 ppm; IR
(neat, cmꢂ1) 2980, 2926, 2853, 1732, 1601, 1474, 1455, 1274, 1245,
1123, 1041, 760, 733. HRMS (ESI) calcd for C14H14FNO2 [MþH]þ
248.1087, found 248.1078.
4.4.10. (1S
ene-1-carbonitrile (4j). Yield: 47%, light yellow oil, 1H NMR
(400 MHz, CDCl3):
*
,5S
*
)-2-(2-Methoxyphenyl)-3-aza-bicyclo[3.1.0]hex-2-
4.4.4. (1S
carbonitrile (4d). Yield: 66%, colourless oil, 1H NMR (400 MHz,
CDCl3):
1.003 (1H, t, J¼5.2 Hz), 1.892 (1H, dd, J¼4.4, 8.8 Hz),
*
,5S )-2-Phenyl-3-aza-bicyclo[3.1.0]hex-2-ene-1-
*
d
1.015 (1H, t, J¼5.2 Hz), 1.812 (1H, dd, J¼4.8,
d
8.4 Hz), 2.760e2.815 (1H, m), 3.974 (3H, s), 4.022 (1H, dd, J¼1.2,
17.6 Hz), 4.132 (1H, dd, J¼6, 17.6 Hz), 6.994e7.030 (2H, m), 7.464
(1H, dt, J¼1.6, 7.6 Hz), 7.645 (1H, dd, J¼1.6, 7.6 Hz) ppm. 13C NMR
2.798e2.853 (1H, m), 4.093 (1H, d, J¼18 Hz), 4.239 (1H, dd, J¼6,
18 Hz), 7.457e7.541 (3H, m), 7.980 (2H, dd, J¼1.6, 8.4 Hz) ppm. 13
C
NMR (100 MHz, CDCl3):
d
22.95, 24.74, 29.81, 62.07, 118.69, 128.27,
(100 MHz, CDCl3): d 22.55, 28.49, 30.11, 55.66, 61.53, 111.43, 118.95,
128.77, 131.39, 131.52, 168.54 ppm; IR (neat, cmꢂ1) 2924, 2852,
2234, 1603, 1575, 1449, 1332, 1011, 999, 776, 696. HRMS (ESI) calcd
for C12H10N2 [MþH]þ 183.0922, found 183.0915.
120.89, 121.34, 130.70, 132.73, 158.33, 168.50 ppm; IR (neat, cmꢂ1
)
3395, 2921, 2849, 2235, 1601, 1464, 1272, 1247, 1023, 760. HRMS
(ESI) calcd for C13H12N2O [MþH]þ 213.1028, found 213.1021.
4.4.5. (1S
carbonitrile (4e). Yield: 74%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
0.984 (1H, t, J¼5.2 Hz), 1.872 (1H, dd, J¼4.4, 8.8 Hz), 2.411
*
,5S
*
)-2-p-Tolyl-3-aza-bicyclo[3.1.0]hex-2-ene-1-
4.4.11. (1S
1-carbonitrile (4k). Yield: 81%, colourless oil, 1H NMR (400 MHz,
CDCl3):
0.999 (1H, t, J¼5.2 Hz), 1.893 (1H, dd, J¼4.4, 8.8 Hz),
*
,5S
*
)-2-(4-Chlorophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
d
d
(1H, s), 2.776e2.830 (1H, m), 4.068 (1H, d, J¼18 Hz), 4.215 (1H, dd,
2.814e2.868 (1H, m), 4.087 (1H, d, J¼18 Hz), 4.232 (1H, dd, J¼6,
J¼6, 18 Hz), 7.2811 (2H, d, J¼8 Hz), 7.870 (2H, d, J¼8 Hz) ppm. 13
C
18 Hz), 7.456 (2H, dd, J¼1.6, 6.8 Hz), 7.922 (2H, d, J¼8.8 Hz) ppm. 13
C
NMR (100 MHz, CDCl3):
d
21.50, 22.92, 24.71, 29.77, 61.91, 118.82,
NMR (100 MHz, CDCl3): d 22.94, 24.63, 29.98, 62.09, 118.44, 129.06,
128.23, 128.70, 129.46, 142.00, 168.40 ppm; IR (neat, cmꢂ1) 2924,
2856, 2233, 1605, 1266, 1512, 1330, 1186, 1044, 1008, 912, 823, 732.
HRMS (ESI) calcd for C13H12N2 [MþH]þ197.1079, found 197.1066.
129.55, 129.82, 137.77, 167.44 ppm; IR (neat, cmꢂ1) 2925, 2852,
2234, 1601, 1492, 1329, 1093, 1007, 841, 734. HRMS (ESI) calcd for
C
12H9ClN2 [MþH]þ 217.0533, found 217.0530.
4.4.6. (1S
carbonitrile (4f). Yield: 82%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
0.990 (1H, t, J¼5.2 Hz), 1.886 (1H, dd, J¼4.4, 8.8 Hz),
*
,5S
*
)-2-m-Tolyl-3-aza-bicyclo[3.1.0]hex-2-ene-1-
4.4.12. (1S
1-carbonitrile (4l). Yield: 65%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
*
,5S
*
)-2-(3-Chlorophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
d
d
1.005 (1H, t, J¼5.2 Hz), 1.907 (1H, dd, J¼4.4, 8.8 Hz),
2.419 (3H, s), 2.788e2.836 (1H, m), 4.079 (1H, d, J¼18 Hz), 4.227
2.822e2.876 (1H, m), 4.101 (1H, d, J¼18 Hz), 4.248 (1H, dd, J¼6,
18 Hz), 7.424 (1H, t, J¼8 Hz), 7.493 (1H, d, J¼8.4 Hz), 7.865 (1H, d,
(1H, dd, J¼6, 18 Hz), 7.351 (2H, m), 7.770 (2H, d, J¼6.4 Hz) ppm. 13
C
Please cite this article in press as: Zhai, S.-X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.043

S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
7
J¼7.6 Hz), 7.964 (1H, s) ppm. 13C NMR (100 MHz, CDCl3):
d
22.96,
2.803e2.857 (1H, m), 4.076 (1H, d, J¼18.4 Hz), 4.266 (1H, dd, J¼6,
18.4 Hz), 6.570 (1H, dd, J¼1.6, 3.6 Hz), 7.270 (1H, d, J¼3.6 Hz), 7.612
24.68, 29.98, 62.14, 118.29, 126.45, 128.16, 130.04, 131.53, 133.03,
134.93, 167.36 ppm; IR (neat, cmꢂ1) 3069, 2925, 2851, 2234, 1605,
1567, 1429, 1324, 1080, 1062, 1000, 794, 730. HRMS (ESI) calcd for
(1H, d, J¼1.6 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 22.93, 24.55,
29.94, 62.21, 111.02, 115.43, 118.13, 145.75, 146.87, 158.35 ppm; IR
(neat, cmꢂ1) 3340, 2924, 2853, 2366, 2236, 1618, 1602, 1481, 1329,
1240, 1045, 1014, 997, 759, 735. HRMS (ESI) calcd for C10H8N2O
[MþH]þ 173.0715, found 173.0705.
C
12H9ClN2 [MþH]þ 217.0533, found 217.0525.
4.4.13. (1S
1-carbonitrile (4m). Yield: 46%, light yellow solid, mp 44e45 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-2-(2-Chlorophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
d
1.202 (1H, t, J¼5.2 Hz), 1.963 (1H, dd,
4.4.19. (1S
1-carbonitrile (4s). Yield: 90%, colourless solid, mp 41e42 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-2-(3-Fluorophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
J¼4.8, 8.4 Hz), 2.914e2.969 (1H, m), 4.098 (1H, dd, J¼1.2, 18 Hz),
4.226 (1H, dd, J¼6, 18 Hz), 7.349 (1H, dt, J¼1.2, 7.6 Hz), 7.429 (1H, dt,
J¼1.6, 8.0 Hz), 7.490 (1H, dd, J¼1.2, 8.0 Hz), 7.605 (1H, dd, J¼1.6,
d
1.002 (1H, t, J¼5.2 Hz), 1.897 (1H, dd,
J¼4.4, 8.8 Hz), 2.816e2.870 (1H, m), 4.096 (1H, d, J¼18 Hz), 4.245
(1H, dd, J¼6, 18.4 Hz), 7.194e7.241 (1H, m), 7.433e7.487 (1H, m),
7.677 (1H, dd, J¼2, 9.6 Hz), 7.776 (1H, d, J¼8.4 Hz) ppm. 13C NMR
7.6 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 24.25, 28.43, 32.00,
62.29, 117.94, 127.09, 130.40, 131.50, 131.73, 131.93, 133.28,
168.82 ppm; IR (neat, cmꢂ1) 2925, 2853, 2236, 1603, 1433, 1328,
1070, 1039, 999, 765, 733. HRMS (ESI) calcd for C12H9ClN2 [MþH]þ
217.0533, found 217.0528.
(100 MHz, CDCl3): d 22.93, 24.71, 29.98, 62.10, 114.85,115.08,118.34,
118.43, 118.64, 124.10, 124.13, 130.36, 130.44, 133.42, 133.50, 161.50,
163.96, 167.40, 167.43 ppm; IR (neat, cmꢂ1) 2926, 2853, 2235, 1608,
1581, 1449, 1329, 1238, 1225, 1153, 1044, 1027, 1001, 970, 869, 792,
733. HRMS (ESI) calcd for C12H9FN2 [MþH]þ 201.0828, found
201.0827.
4.4.14. (1S
1-carbonitrile (4n). Yield: 73%, colourless solid, mp 65e66 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-2-(4-Bromophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
d
1.000 (1H, t, J¼5.2 Hz), 1.895 (1H, dd,
J¼4.4, 8.8 Hz), 2.816e2.870 (1H, m), 4.082 (1H, d, J¼18 Hz), 4.225
(1H, dd, J¼6, 18 Hz), 7.620 (2H, dd, J¼2, 6.8 Hz), 7.851 (2H, d,
Acknowledgements
J¼8.4 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 22.97, 24.61, 30.00,
We are grateful to acknowledge financial support from Lanzhou
University SKLAOC.
62.16, 118.44, 126.30, 129.73, 130.27, 132.06, 167.58 ppm; IR (neat,
cmꢂ1) 3056, 2924, 2852, 2234, 1603, 1591, 1486, 1397, 1328, 1071,
1004, 839, 817, 736. HRMS (ESI) calcd for C12H9BrN2 [MþH]þ
261.0027, found 261.0025.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.08.043.
4.4.15. (1S
1-carbonitrile (4o). Yield: 62%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
*
,5S
*
)-2-(3-Bromophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
d
1.004 (1H, t, J¼5.2 Hz), 1.907 (1H, dd, J¼4.4, 8.8 Hz), 2.848
References and notes
(1H, dd, J¼6, 14 Hz), 4.103 (1H, d, J¼18 Hz), 4.250 (1H, dd, J¼6,
18 Hz), 7.363 (1H, t, J¼8 Hz), 7.647 (1H, d, J¼8.0 Hz), 7.910 (1H, d,
1. (a) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237e294; (b) Clavier, H.; Pellissier,
H. Adv. Synth. Catal. 2012, 354, 3347e3403; (c) Raimondi, W.; Bonne, D.; Ro-
driguez, J. Angew. Chem., Int. Ed. 2012, 51, 40e42; (d) Grossmann, A.; Enders, D.
Angew. Chem., Int. Ed. 2012, 51, 314e325; (e) Platon, M.; Amardeil, R.; Djako-
vitch, L.; Hierso, J. C. Chem. Soc. Rev. 2012, 41, 3929e3968; (f) Tejedor, D.;
J¼7.6 Hz), 8.123 (1H, s) ppm. 13C NMR (100 MHz, CDCl3):
d 22.98,
24.66, 29.99, 62.15, 118.28, 122.96, 126.91, 130.28, 131.07, 133.26,
134.45, 167.26 ppm; IR (neat, cmꢂ1) 2924, 2851, 2234, 1604, 1561,
1426, 1323, 1072, 1000, 792, 737, 721. HRMS (ESI) calcd for
ꢀ
Mendez-Abt, G.; Cotos, L.; Garcia-Tellado, F. Chem. Soc. Rev. 2013, 42, 458e471;
(g) Malacria, M. Chem. Rev. 1996, 96, 289e306; (h) Nicolaou, K. C.; Montagnon,
T.; Snyder, S. A. Chem. Commun. 2003, 551e564; (i) Nicolaou, K. C.; Edmonds, D.
J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134e7186; (j) Enders, D.;
C
12H9BrN2 [MþH]þ 261.0027, found 261.0029.
€
Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570e1581; (k) Dong,
4.4.16. (1S
1-carbonitrile (4p). Yield: 46%, light yellow oil, 1H NMR (400 MHz,
CDCl3):
*
,5S
*
)-2-(2-Bromophenyl)-3-aza-bicyclo[3.1.0]hex-2-ene-
H. R.; Dong, W. J.; Li, R. S.; Hu, Y. M.; Dong, H. S.; Xie, Z. X. Green Chem. 2014, 16,
3454e3457.
d
1.266 (1H, t, J¼5.2 Hz), 1.987 (1H, dd, J¼4.8, 8.8 Hz),
2. (a) Liedtke, A. J.; Keck, P. R. W. E. F.; Lehmann, F.; Koeberle, A.; Werz, O.; Laufer,
S. A. J. Med. Chem. 2009, 52, 4968e4972; (b) Calas, M.; Ouattara, M.; Piquet, G.;
Ziora, Z.; Bordat, Y.; Ancelin, M. L.; Escale, R.; Vial, H. J. Med. Chem. 2007, 50,
2.942e2.998 (1H, m), 4.097 (1H, d, J¼18 Hz), 4.236 (1H, dd, J¼6,
18 Hz), 7.341 (1H, dt, J¼1.6, 7.6 Hz), 7.401 (1H, dt, J¼1.2, 7.6 Hz),
€
6307e6315; (c) Grunwald, C.; Rundfeldt, C.; Lankau, H.-J.; Arnold, T.; Hofgen,
7.557 (1H, dd, J¼2, 7.6 Hz), 7.681 (1H, dd, J¼1.2, 8.0 Hz) ppm. 13
C
N.; Dost, R.; Egerland, U.; Hofmann, H.-J.; Unverferth, K. J. Med. Chem. 2006, 49,
1855e1866; (d) Lee, M.; Lee, Y.-J.; Park, E.; Park, Y.; Ha, M. W.; Hong, S.; Lee, Y.-
J.; Kim, T.-S.; Kim, M.-H.; Park, H.-G. Bioorg. Med. Chem. 2013, 11, 2039e2046;
(e) Altmann, E.; Hommel, U.; Lorthiois, E. L. J.; Maibaum, J. K.; Ostermann, N.;
Quancard, J.; Randl, S. A.; Simic, O.; Vulpetti, A.; Rogel. WO 2012/093101. (f) Ji,
K.; Zhu, H.; Yang, F.; Shaukat, A.; Xia, X.; Yang, Y.; Liu, X.; Liang, Y. J. Org. Chem.
2010, 75, 5670e5678; For the reviews, see: (g) Zeni, G.; Larock, R. C. Chem. Rev.
2004, 104, 2285e2310.
NMR (100 MHz, CDCl3): d 25.05, 28.27, 32.42, 62.38, 117.90, 121.83,
127.57, 131.73, 131.93, 133.65, 133.85, 169.62 ppm; IR (neat, cmꢂ1
)
2926, 2852, 2236, 1604, 1430, 1328, 1080, 1029, 999, 911, 765,
734. HRMS (ESI) calcd for C12H9BrN2 [MþH]þ 261.0027, found
261.0024.
3. (a) Kollmeyer, W. D.; Calif, M. U.S. Patent 4,183,857, 1980; (b) Mijts, B.; Muley, S.;
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Colbeck, J.; Munger, J. D., Jr.; Mavinhalli, J.; Sheldon, R. WO 2010/008828; (c)
Kwok, D. -I.; Lee, H. -C.; Zavialov, I. A. WO 2009/073380.
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Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12, 3682e3685; (c) Chiba, S.; Zhang, L.; Lee,
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Iida, S. Synlett 2006, 2159e2175; (b) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354e362; Some examples of I2-catalyzed reactions: (c) Ji, K.
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Chem.dEur. J. 2010, 16, 6151e6154; (d) Pedras, M. S. C.; Jha, M. J. Org. Chem.
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4.4.17. (1S
carbonitrile (4q). Yield: 64%, colourless solid, mp 115e116 ꢀC, 1H
NMR (400 MHz, CDCl3):
*
,5S
*
)-2-(4-Iodophenyl)-3-aza-bicyclo[3.1.0] hex-2-ene-1-
d
0.994 (1H, t, J¼5.2 Hz), 1.892 (1H, dd,
J¼4.4, 8.8 Hz), 2.836 (1H, dd, J¼6, 14.4 Hz), 4.076 (1H, d, J¼18 Hz),
4.219 (1H, dd, J¼6, 18 Hz), 7.701 (2H, d, J¼8.4 Hz), 7.835 (2H, d,
J¼8.8 Hz) ppm. 13C NMR (100 MHz, CDCl3):
d 22.98, 24.58, 29.99,
62.18, 98.62, 118.43, 129.73, 130.82, 138.04, 167.80 ppm; IR (neat,
cmꢂ1) 2924, 2853, 2234, 1602, 1585, 1485, 1327, 1187, 1060, 1000,
910, 836, 817, 732. HRMS (ESI) calcd for C12H9IN2 [MþH]þ 308.9889,
found 308.9885.
4.4.18. (1S
carbonitrile (4r). Yield: 82%, colourless oil, 1H NMR (400 MHz,
CDCl3):
0.978 (1H, t, J¼5.2 Hz), 1.834 (1H, dd, J¼4.8, 8.8 Hz),
*
,5S )-2-(Furan-2-yl)-3-aza-bicyclo[3.1.0]hex-2-ene-1-
*
d
Please cite this article in press as: Zhai, S.-X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.043

8
S.-X. Zhai et al. / Tetrahedron xxx (2014) 1e8
2632e2633; (f) He, Z.; Liu, W.; Li, Z. Chem. Asian J. 2011, 6, 1340e1343; (g) He,
10. Selected reviews: (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273e5308; (b) Kitagawa, O.; Taguchi, T.
Synlett 1999, 1191e1199; (c) Robin, S.; Rousseau, G. Tetrahedron 1998, 54,
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Please cite this article in press as: Zhai, S.-X.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.08.043